This project will utilize newly developed assays for a battery of oxidative DNA adducts to better define dose and time responses for oxidative stress induced by exposure to PCBs and TCDD using liver and lung samples from 13, 30 and 52-week tissues from Sprague-Dawley rats exposed to pentachlorodibenzofuran, PCB 118, or mixtures of TCDD, PeCDF and PCB 126 from the NTP Toxic Equivalency Factor (TEF) studies. These studies will demonstrate the relationships between endogenous DNA adducts and carcinogenesis and determine if the """"""""oxidative stress"""""""" Mode of Action for this important set of nongenotoxic chemicals is supported. Endogenous DNA adducts can be converted to mutations if DNA replication takes place before repair. Unlike DNA adducts, mutations cannot be repaired and are heritable in the progeny of the originally mutated cell. We have shown that endogenous DNA lesions are always present in genomic DNA, attaining >40,000 adducts per cell. Since most of these lesions are potentially mutagenic, this nonzero background of endogenous DNA damage is a likely cause of the nonzero spontaneous background mutation rate. We will develop new methods for studying mutations using the PIG gene in DT-40 cells and will employ this system to evaluate the dose-response for mutations resulting from chemicals that form DNA adducts identical to endogenously formed adducts in cells and tissues. This research will provide highly informative scientific data to be used in future cancer risk assessments, rather than relying on linear default science policy decisions that may not provide additional protection to public health, but pose expensive and often non-attainable clean-up levels for Superfund sites. Finally, we will collaborate with Projects 2, 3, 4 and 5 respectively, to determine the role of oxidative stress in the toxicity of trichloroethylene;identify critical DNA response pathways for cadmium;evaluate CAFLUX and CALUX cell biological responses to samples of environmental contaminants;and examine toxicity and DNA damage response pathways of original extracts and their fractionated and purified samples of PAH mixtures that have undergone bioremediation.
This research will clarify the role of oxidative stress in the toxicity and carcinogenicity of TCDD and PCBs and demonstrate the role of endogenous DNA adducts in mutagenesis. Using these data, it will determine critical dose-response relationships necessary for science-based low dose extrapolation of cancer risk assessments.
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